Arsenic is a toxin and carcinogen found in water, soil, food, and air. The natural source of arsenic is from weathering of arsenic-rich geologic formations. Arsenic also derives from human agricultural and industrial sources. Arsenic is used in pesticides, wood preservatives, and manufacturing of glass, paper, and semiconductors. This toxin is released into the environment during metal smelting, mining, fossil fuel burning, and incineration. Arsine gas has been used as a chemical warfare agent. Inorganic forms of arsenic, including arsenite (trivalent) and arsenate (pentavalent), are more toxic than organic forms, including methylarsonate and dimethylarsinate. Methyltransferases in humans and animals methylate inorganic arsenic, facilitating its excretion. (Shalat, S. L. et al. (1996) J. Toxicol. Env. Health 48:253-272; Jager, J. W. and Ostrosky-Wegman, P. (1997) Mutat. Res. 386:181-184; and Graeme, K. A. and Pollack, Jr., C. V. (1998) J. Emerg. Med. 16:45-56.)
Acute arsenic poisoning can be fatal, killing by impairment of cellular respiration in the case of arsenite and arsenate, or by hemolysis in the case of arsine gas. The effects of chronic low arsenic exposure are of interest due to increasing pollution of water, air, and food with arsenic from industrial and agricultural sources. Chronic arsenic exposure is associated with skin and lung cancers in humans, but not in animals. Arsenite causes chromosomal aberrations, sister chromatid exchanges, and cell transformation, and acts as a comutagen with ultraviolet light and the alkylating agent N-methyl-N-nitrosourea. (Wang, Z. and Rossman, T. G. (1993) Toxicol. Appl. Pharmacol. 118:80-86.) Arsenic can cross the placenta and selectively accumulate in the fetal neuroepithelium during early embryogenesis. Maternal or paternal exposure to arsenic is associated with spontaneous abortion, stillbirth, and congenital malformations and developmental impairment in the infant. Neural tube defects such as dysraphic spina bifida and anencephaly are predominant. (Shalat, supra.) Other effects in humans include peripheral neuropathy, microangiopathy, bone marrow and immune suppression, and cardiovascular disease. (Jager, supra; and Shalat, supra.)
Arsenic compounds exert their effects by a variety of means. Arsenite reacts with thiol groups in macromolecules such as proteins and nucleic acids. Glycolytic and .beta.-oxidation enzymes are inhibited by this reaction, which may cause increased and unregulated cell death. This cell death may cause developmental defects because reduced cell proliferation is associated with neural tube defects in mice. (Shalat, supra.) Inorganic arsenic impairs the assembly and disassembly of microtubules and may interfere with mitotic spindle formation, embryonic cell division, and neural tube formation. Arsenite reaction with the thiols present in histones and nucleic acids may cause the chromosomal damage associated with arsenic exposure. Arsenate can substitute for phosphate in enzymatic reactions, forming acyl arsenates. However, acyl arsenates are less stable than the corresponding phosphates and decompose rapidly, inhibiting glycolytic and oxidative phosphorylation enzymes. (Wang, Z. et al. (1996) Toxicol. Appl. Pharmacol. 137:112-119.)
To understand the mechanism of arsenic toxicity and carcinogenicity, studies involving arsenite resistance in cultured Chinese hamster and human cells have been undertaken. Hamster cells become tolerant to toxic levels of arsenite after pretreatment with low levels. Stable arsenite-resistant hamster cells have also been selected. Expression cloning of arsenite-resistance genes from Chinese hamster identified two genes, ars1 and ars2. Ars1 is similar to ubiquitin, while ars2 is novel. (Rossman, T. G. and Wang, Z., unpublished; Wang (1993) supra; and Rossman, T. G. et al. (1997) Mutat. Res. 386:307-314.) Human cells could not be induced to become arsenite-tolerant under the conditions used for hamster cells. This result may explain why humans develop tumors after arsenite exposure, while rodents do not. The researchers concluded that humans may be unable to induce one or more protective proteins in response to arsenite. Possible mechanisms for arsenite resistance include upregulation of an arsenic efflux pump, increased rates of transformation of arsenite to arsenate and organic forms, increased binding to proteins, and elevation of glutathione levels and glutathione S-transferase activity. (Wang, (1993) supra; and Rossman, (1997) supra.)
The discovery of a new human arsenite-resistance protein and the polynucleotides encoding it satisfies a need in the art by providing new compositions which are usefull in the diagnosis, treatment, and prevention of cancer, developmental disorders, reproductive disorders, and autoimmune/inflammatory disorders.